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Published online 15 December 2003. doi:10.1083/jcb.200307178
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© The Rockefeller University Press, 0021-9525/2003/12/1385 $8.00
The Journal of Cell Biology, Volume 163, Number 6, 1385-1395

Article

 Signal-dependent distribution of cell surface P-selectin in clathrin-coated pits affects leukocyte rolling under flow

Hendra Setiadi1 and Rodger P. McEver1,2

1 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
2 Department of Biochemistry and Molecular Biology and Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104

Address correspondence to Rodger P. McEver, Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th St., Oklahoma City, OK 73104. Tel.: (405) 271-6480. Fax: (405) 271-3137. email: rodger-mcever{at}omrf.ouhsc.edu

Flowing leukocytes roll on P-selectin that is mobilized from secretory granules to the surfaces of endothelial cells after stimulation with histamine or thrombin. Before it is internalized, P-selectin clusters in clathrin-coated pits, which enhances its ability to support leukocyte rolling. We found that thrombin and histamine induced comparable exocytosis of P-selectin on endothelial cells. However, compared with histamine, thrombin decreased the recruitment of P-selectin into clathrin-coated pits, slowed the internalization of P-selectin, and reduced the number and stability of neutrophils rolling on P-selectin. Significantly more RhoA was activated in thrombin- than in histamine-stimulated endothelial cells. Inhibitors of RhoA or its effector, Rho kinase, reversed thrombin's ability to inhibit the internalization and adhesive function of P-selectin in endothelial cells. Experiments with transfected cells confirmed that the inhibitory actions of thrombin and Rho kinase on P-selectin required its cytoplasmic domain. Thus, a signaling event affects both the function and clearance of a protein that enters the constitutive clathrin-mediated endocytic pathway.

Key Words: selectin; endocytosis; endothelial cell; thrombin; RhoA

Abbreviations used in this paper: C3T, exoenzyme C3 transferase; HUVEC, human umbilical vein endothelial cells; PSGL-1, P-selectin glycoprotein ligand-1; sP-selectin, recombinant soluble P-selectin; TRAP, thrombin receptor-activating peptide.


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